Cancer Relevance and Scientific Rationale: Childhood cancer survivors are at a life-long risk of chronic health conditions; by age 50, the cumulative incidence of life-threatening/fatal chronic health conditions is 53%. The two leading causes of premature mortality in childhood cancer survivors are radiation-related subsequent neoplasms (SNs) and anthracycline-related cardiac dysfunction (CD). Radiation and anthracyclines are both used in >60% of children with cancer, and there are no plans in the foreseeable future to eliminate these agents. Although there is a dose-response relation between radiation and SN and between anthracyclines and CD (regardless of the underlying primary cancer), there is significant inter-patient variability in the risk, suggesting the moderating role of genetic predisposition. The high burden of morbidity coupled with the inter-individual variability in risk, suggests a need and an opportunity to identify patients at highest risk for treatment-related morbidity, such that targeted interventions can be instituted. Broad Plan: This application harnesses and merges novel concepts from the field of molecular biology, pharmacogenomics and cancer survivorship to identify cancer patients by their personal risk of SN or CD. This award also attempts to understand the molecular pathogenesis of these complications to inform future development of targeted prevention/therapeutic strategies. The necessary infrastructure for the proposed research, including banked, annotated biospecimens (n=13,450) and pre-existing collaborations with the necessary expertise will be leveraged in this application. The goals are to: i) develop a risk prediction model for radiation-related SN and anthracycline-related CD in childhood cancer survivors; ii) replicate the optimized model in an independent cohort of childhood cancer survivors; iii) apply the optimized model to newly-diagnosed children with cancer to predict the risk of incident SN/CD; iv) determine the functional relevance of the genetic signatures. Qualifications: I am the founding Director of the Institute for Cancer Outcomes and Survivorship at the University of Alabama at Birmingham. I have over 20y of experience conducting cancer outcomes research that bridges the fields of oncology, epidemiology and genetics. Since 2000, I have been charged with shaping the pediatric oncology survivorship research agenda within the Children's Oncology Group ? an NCI-supported clinical trials group, devoted exclusively to pediatric cancer research across 220 centers. I am currently serving as chair-elect for the ASCO survivorship committee. I am a Leukemia Lymphoma Scholar, a recipient of the Frank H Oski award, and am an elected member of the American Society of Clinical Investigation, and the Association for American Physicians. I have been continuously funded by NCI since 2000. With over 235 peer-reviewed publications and 15,220 citations (9,300 since 2012), my Google Scholar H-INDEX is 66 (54 since 2012) and my i10-index is 182 (167 since 2012). I am fully committed to improving the long-term health of our childhood cancer survivors, and I strongly believe that findings from this application will accelerate the pace to reduce the burden of morbidity in this population.